Hypertension, Obesity & Overweight
Conditions
Keywords
hypertension, obesity, overweight, tirzepatide, GLP-1
Brief summary
Hypertension is the leading risk factor for death globally, affecting approximately 30% of adults in the United Kingdom. Obesity is also a serious and ongoing epidemic, with global obesity rates having more than tripled in men and doubled in women, since 1975. In the United Kingdom, 64% of the adult population are overweight or obese. Hypertension and obesity share a well-established association, with obesity being responsible for the development of hypertension in 40-78% of cases. In young adults, this link between body size and blood pressure (BP) is much stronger that in older adults. Since overweight and obesity are among the most common and modifiable causes of high BP, weight loss induced by lifestyle-changes is recommended for overweight or obese patients with hypertension. However, lifestyle interventions, even when successful, result in only moderate weight loss, which is not maintained in the majority of cases. A meta-analysis of randomised controlled trials demonstrated that lifestyle-interventions lead to an average net weight reduction of 5.1 kg, accompanied by a significant, but modest, \ 4 mmHg reduction in BP. Weight loss interventions could play a crucial role in the treatment of obesity-related hypertension in young adults. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, originally developed for the treatment of type 2 diabetes, are safe and clinically effective anti-obesity drugs. Recent data show a 10-20% placebo-adjusted reduction in body weight in overweight or obese adults without diabetes using the GLP-1 analogue semaglutide or the dual GLP-1/GIP receptor agonist tirzepatide, with the majority of weight loss achieved within the initial six months. The substantial weight loss induced by these drugs is accompanied by a significant reduction in BP. Two recent meta-analyses showed that semaglutide is associated with a \ 5 mmHg placebo-adjusted reduction in clinic systolic BP (SBP). A sub-study of the SURMOUNT-1 trial reported a \ 10 mmHg reduction in 24-h ambulatory SBP with tirzepatide. Most participants in these studies were normotensive or had well-controlled hypertension. Furthermore, antihypertensive medication use declined amongst those receiving anti-obesity drugs meaning the BP-lowering effect of weight loss, elicited by these drugs, is probably underestimated. These data suggest that the new anti-obesity drugs could be effective in managing overweight or obesity-related hypertension. Furthermore, it may be possible to cure hypertension in at least some young adults, removing the need for life-long antihypertensive treatment. However, the magnitude and time course of BP reduction elicited by these new anti-obesity drugs remain uncertain. The primary aim of this feasibility study is to assess the extent and trajectory of BP reduction achieved through intensive weight loss in overweight or obese adults with stage 1 hypertension and compare this to current standard of care measures which uses anti-hypertensive medications and lifestyle advice. The study will utilise a modified trial within cohort approach, using patients based within the clinical pharmacology/hypertension service at Addenbrooke's Hospital, Cambridge.
Interventions
DRUGTirzepatide
2.5mg for 4 weeks, 5mg for 4 weeks, 7.5mg for 4 weeks, 10mg for 12 weeks
Anti-hypertensive drug therapy as per local and national guidelines
Sponsors
Cambridge University Hospitals NHS Foundation Trust
National Institute for Health Research, United Kingdom
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study will utilise a modified trial within cohort (TwiC) design for patients under the hypertension/clinical pharmacology clinic. Those who meet the eligibility criteria for randomisation will be randomised to being approached for either: (i) 6 months of treatment with a combined GLP-1/GIP receptor agonist, Tirzepatide \[Group A - Weight loss arm\] (ii) Standard anti-hypertensive treatment and attendance at a 6-month combined research/clinical follow-up visit \[Group B - Standard of Care (SoC) arm\].
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
Eligibility criteria for randomisation Inclusion Criteria: * Aged 18 to 40 years (inclusive) * Body mass index (BMI) ≥27 kg/m2 * Clinical diagnosis of primary (essential) hypertension as per NICE guidance * Unattended brachial SBP ≥135 and/or DBP ≥85 mmHg and \<160/100 mmHg * Maximum of one antihypertensive medication
Exclusion criteria
• Anything in medical notes suggesting unsuitable in the opinion of the investigator Eligibility criteria for participation in weight loss arm Inclusion criteria: * Written informed consent * Aged 18 to 40 years (inclusive) * Body mass index ≥27 kg/m2 * Clinical diagnosis of primary (essential) hypertension as per NICE guidance * Unattended brachial SBP ≥135 and/or DBP ≥85 mmHg and \<160/100 mmHg * Maximum of one antihypertensive medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ambulatory systolic blood pressure | Baseline to week 24 | Change in daytime ambulatory systolic blood pressure in the weight loss arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ambulatory diastolic blood pressure | Baseline to week 24 | Change in daytime ambulatory diastolic blood pressure in the weight loss arm |
| Clinic systolic blood pressure | Baseline to week 24 | Changes in clinic systolic blood pressure in the weight loss arm |
| Clinic diastolic blood pressure | Baseline to week 24 | Changes in clinic diastolic blood pressure in the weight loss arm |
| Clinic mean arterial pressure | Baseline to week 24 | Changes in clinic mean arterial pressure in the weight loss arm |
| Unattended systolic blood pressure | Baseline to week 24 | Changes in unattended systolic blood pressure in the weight loss arm |
| Unattended diastolic blood pressure | Baseline to week 24 | Changes in unattended diastolic blood pressure in the weight loss arm |
| Unattended mean arterial pressure | Baseline to week 24 | Changes in unattended mean arterial pressure in the weight loss arm |
| Body weight | Baseline to week 24 | Changes in body weight in the weight loss arm |
| Body fat | Baseline to week 24 | Changes in body fat in the weight loss arm |
| Waist:hip ratio | Baseline to week 24 | Changes in waist:hip ratio in the weight loss arm |
| Cardiac output | Baseline to week 24 | Changes in cardiac output in the weight loss arm |
| Peripheral vascular resistance | Baseline to week 24 | Changes in peripheral vascular resistance in the weight loss arm |
| Pulse wave analysis / pulse wave velocity | Baseline to week 24 | Changes in markers of pulse wave analysis and pulse wave velocity in the weight loss arm |
| Heart rate variability | Baseline to week 24 | Changes in heart rate variability in the weight loss arm |
| Renin | Baseline to week 24 | Changes in plasma renin in the weight loss arm |
| Aldosterone | Baseline to week 24 | Changes in plasma aldosterone in the weight loss arm |
| Plasma metanephrines | Baseline to week 24 | Changes in plasma metanephrines in the weight loss arm |
| Leptin | Baseline to week 24 | Changes in leptin in the weight loss arm |
| Insulin | Baseline to week 24 | Changes in plasma insulin in the weight loss arm |
| Lipid profile | Baseline to week 24 | Changes in the lipid profile in the weight loss arm |
| HbA1C | Baseline to week 24 | Changes in HbA1C in the weight loss arm |
| Estimated glomerular filtration rate | Baseline to week 24 | Changes in eGFR in the weight loss arm |
| N-terminal pro-B-type natriuretic peptide | Baseline to week 24 | Changes in NT-proBNP in the weight loss arm |
| Urine albumin:creatinine ratio | Baseline to week 24 | Change in urine albumin:creatinine ratio in the weight loss arm |
| 24-hour urine sodium | Baseline to week 24 | Change in 24-hour urine sodium in the weight loss arm |
| 24-hour urine aldosterone | Baseline to week 24 | Change in 24-hour urine aldosterone in the weight loss arm |
| Antihypertensive medications | Baseline to week 24 | Change in number of antihypertensive medications |
| Quality of life measures | Baseline to week 24 | Changes in quality of life questionnaire scores in the weight loss arm |
| Ambulatory systolic blood pressure | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) | Between-group comparison in ambulatory sytolic blood pressure |
| Plasma renin | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) | Between-group comparison in plasma renin |
| Plasma aldosterone | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) | Between-group comparison in plasma aldosterone |
| Number of antihypertensive medications | Change from baseline to week 24 (weight loss arm) and 6 months (standard of care arm) | Between-group comparison in the number of anti-hypertensive medications |
Countries
United Kingdom
Outcome results
None listed